tbuckley/cabot-search huggingface dataset:
A genome-wide CRISPR/Cas9 screen identifies DNA-PK as a sensitiser to <sup>177</sup>Lutetium-DOTA-octreotate radionuclide therapy
Authors: Kelly Waldeck, Jessica Van Zuylekom, Carleen Cullinane, Twishi Gulati, Kaylene J. Simpson, Richard W. Tothill, Benjamin Blyth, Rodney J. Hicks
Journal: Theranostics (2023)

Peptide receptor radionuclide therapy (PRRT) using 177 Lutetium-DOTA-octreotate (LuTate) for neuroendocrine tumours (NET) is now an approved treatment available in many countries, though primary or secondary resistance continue to limit its effectiveness or durability.We hypothesised that a genome-wide CRISPR/Cas9 screen would identify key mediators of response to LuTate and gene targets that might offer opportunities for novel combination therapies for NET patients.Methods: We utilised a genome-wide CRISPR-Cas9 screen in LuTate-treated cells to identify genes that impact on the sensitivity or resistance of cells to LuTate.Hits were validated through single-gene knockout.LuTate-resistant cells were assessed to confirm LuTate uptake and retention, and persistence of somatostatin receptor 2 (SSTR2) expression.Gene knockouts conferring LuTate sensitivity were further characterised by pharmacological sensitisation using specific inhibitors and in vivo analysis of the efficacy of these inhibitors in combination with LuTate. Results:The CRISPR-Cas9 screen identified several potential targets for both resistance and sensitivity to PRRT.Two gene knockouts which conferred LuTate resistance in vitro, ARRB2 and MVP, have potential mechanisms related to LuTate binding and retention, and modulation of DNA-damage repair (DDR) pathways, respectively.The screen showed that sensitivity to LuTate treatment in vitro can be conferred by the loss of a variety of genes involved in DDR pathways, with loss of genes involved in Non-Homologous End-Joining (NHEJ) being the most lethal.Loss of the key NHEJ gene, PRKDC (DNA-PK), either by gene loss or inhibition by two different inhibitors, resulted in significantly reduced cell survival upon exposure of cells to LuTate.In SSTR2-positive xenograft-bearing mice, the combination of nedisertib (a DNA-PK specific inhibitor) and LuTate produced a more robust control of tumour growth and increased survival compared to LuTate alone.Conclusions: DDR pathways are critical for sensing and repairing radiation-induced DNA damage, and our study shows that regulation of DDR pathways may be involved in both resistance and sensitivity to PRRT.Additionally, the use of a DNA-PK inhibitor in combination with LuTate PRRT significantly improves the efficacy of the treatment in pre-clinical models, providing further evidence for the clinical efficacy of this combination.
Financial hardship in families of children or adolescents with cancer: a systematic literature review
Authors: Julie Ritter, Savannah Allen, Phillip D Cohen, Andrés Felipe Fajardo, Kelsey Marx, Patrícia Loggetto, Carmen Auste, Hedley Lewis, Karla Emília de Sá Rodrigues, Sharmeen Hussain, Ayomide Omotola, Nancy S Bolous, Harsha Thirumurthy, Beverley M Essue, Eva Steliarova-Foucher, I-Chan Huang, Filip Meheus, Nickhill Bhakta
Journal: The Lancet Oncology (2023)
A paintable and adhesive hydrogel cardiac patch with sustained release of ANGPTL4 for infarcted heart repair
Authors: Mingyu Lee, Yong Sook Kim, Junggeon Park, Goeun Choe, Sanghun Lee, Bo Gyeong Kang, Ju Hee Jun, Yoonmin Shin, Minchul Kim, Youngkeun Ahn, Jae Young Lee
Journal: Bioactive Materials (2023)

The infarcted heart undergoes irreversible pathological remodeling after reperfusion involving left ventricle dilation and excessive inflammatory reactions in the infarcted heart, frequently leading to fatal functional damage. Extensive attempts have been made to attenuate pathological remodeling in infarcted hearts using cardiac patches and anti-inflammatory drug delivery. In this study, we developed a paintable and adhesive hydrogel patch using dextran-aldehyde (dex-ald) and gelatin, incorporating the anti-inflammatory protein, ANGPTL4, into the hydrogel for sustained release directly to the infarcted heart to alleviate inflammation. We optimized the material composition, including polymer concentration and molecular weight, to achieve a paintable, adhesive hydrogel using 10% gelatin and 5% dex-ald, which displayed in-situ gel formation within 135 s, cardiac tissue-like modulus (40.5 kPa), suitable tissue adhesiveness (4.3 kPa), and excellent mechanical stability. ANGPTL4 was continuously released from the gelatin/dex-ald hydrogel without substantial burst release. The gelatin/dex-ald hydrogel could be conveniently painted onto the beating heart and degraded in vivo. Moreover, in vivo studies using animal models of acute myocardial infarction revealed that our hydrogel cardiac patch containing ANGPTL4 significantly improved heart tissue repair, evaluated by echocardiography and histological evaluation. The heart tissues treated with ANGPTL4-loaded hydrogel patches exhibited increased vascularization, reduced inflammatory macrophages, and structural maturation of cardiac cells. Our novel hydrogel system, which allows for facile paintability, appropriate tissue adhesiveness, and sustained release of anti-inflammatory drugs, will serve as an effective platform for the repair of various tissues, including heart, muscle, and cartilage.
Phase III Trial of Carboplatin and Paclitaxel Compared With Cisplatin and Paclitaxel in Patients With Optimally Resected Stage III Ovarian Cancer: A Gynecologic Oncology Group Study
Authors: Robert F. Ozols, Brian N. Bundy, Benjamin E. Greer, Jeffrey M. Fowler, Daniel Clarke-Pearson, Robert A. Burger, Robert S. Mannel, Koen DeGeest, Ellen M. Hartenbach, Rebecca Baergen
Journal: Journal of Clinical Oncology (2023)

In randomized trials the combination of cisplatin and paclitaxel was superior to cisplatin and cyclophosphamide in advanced-stage epithelial ovarian cancer. Although in nonrandomized trials, carboplatin and paclitaxel was a less toxic and highly active combination regimen, there remained concern regarding its efficacy in patients with small-volume, resected, stage III disease. Thus, we conducted a noninferiority trial of cisplatin and paclitaxel versus carboplatin and paclitaxel in this population.
Tumour stage, treatment, and survival of women with high-grade serous tubo-ovarian cancer in UKCTOCS: an exploratory analysis of a randomised controlled trial
Authors: Usha Menon, Aleksandra Gentry-Maharaj, Matthew Burnell, Andy Ryan, Naveena Singh, Ranjit Manchanda, Jatinderpal K Kalsi, Robert Woolas, Rupali Arora, Laura Casey, Anne Dawnay, Aarti Sharma, Karin Williamson, Sophia Apostolidou, Lesley Fallowfield, Alistair J McGuire, Stuart Campbell, Steven J Skates, Ian J Jacobs, Mahesh K B Parmar
Journal: The Lancet Oncology (2023)

In UKCTOCS, there was a decrease in the diagnosis of advanced stage tubo-ovarian cancer but no reduction in deaths in the multimodal screening group compared with the no screening group. Therefore, we did exploratory analyses of patients with high-grade serous ovarian cancer to understand the reason for the discrepancy.
Aspirin synergizes with mineral particle-coated macroporous scaffolds for bone regeneration through immunomodulation
Authors: Ni Su, Cassandra Villicana, Carl Zhang, Jeehee Lee, Sauradeep Sinha, Andrew Yang, Fan Yang
Journal: Theranostics (2023)

Rationale: Mineral particles have been widely used in bone tissue engineering scaffolds due to their osteoconductive and osteoinductive properties.Despite their benefits, mineral particles can induce undesirable inflammation and subsequent bone resorption.Aspirin (Asp) is an inexpensive and widely used anti-inflammatory drug.The goal of this study is to assess the synergistic effect of Asp and optimized mineral particle coating in macroporous scaffolds to accelerate endogenous bone regeneration and reduce bone resorption in a critical-sized bone defect model.Methods: Four commonly used mineral particles with varying composition (hydroxyapatite v.s.tricalcium phosphate) and size (nano v.s.micro) were used.Mineral particles were coated onto gelatin microribbon (µRB) scaffolds.Macrophages (Mφ) were cultured on gelatin µRB scaffolds containing various particles, and Mφ polarization was assessed using PCR and ELISA.The effect of conditioned medium from Mφ on mesenchymal stem cell (MSC) osteogenesis was also evaluated in vitro.Scaffolds containing optimized mineral particles were then combined with varying dosages of Asp to assess the effect in inducing endogenous bone regeneration using a critical-sized cranial bone defect model.In vivo characterization and in vitro cell studies were performed to elucidate the effect of tuning Asp dosage on Mφ polarization, osteoclast (OC) activity, and MSC osteogenesis.Results: Micro-sized tricalcium phosphate (mTCP) particles were identified as optimal in promoting M2 Mφ polarization and rescuing MSC-based bone formation in the presence of conditioned medium from Mφ.When implanted in vivo, incorporating Asp with mTCP-coated µRB scaffolds significantly accelerated endogenous bone formation in a dose-dependent manner.Impressively, mTCP-coated µRB scaffolds containing 20 µg Asp led to almost complete bone healing of a critical-sized cranial bone defect as early as week 2 with no subsequent bone resorption.Asp enhanced M2 Mφ polarization, decreased OC activity, and promoted MSC osteogenesis in a dosage-dependent manner in vivo.These results were further validated using in vitro cell studies.Conclusions: Here, we demonstrate Asp and mineral particle-coated microribbon scaffold provides a promising therapy for repairing critical-sized cranial bone defects via immunomodulation.The leading formulation supports rapid endogenous bone regeneration without the need for exogenous cells or growth factors, making it attractive for translation.Our results also highlight the importance of optimizing mineral particles and Asp dosage to achieve robust bone healing while avoiding bone resorption by targeting Mφ and OCs.
Evaluation of FAPI PET imaging in gastric cancer: a systematic review and meta-analysis
Authors: Dan Ruan, Liang Zhao, Jiayu Cai, Weizhi Xu, Long Sun, Jiayi Li, Jingjing Zhang, Xiaoyuan Chen, Haojun Chen
Journal: Theranostics (2023)

Purpose: Recent studies suggest that 68 Ga-FAPI PET/CT demonstrated superiority over 18 F-FDG PET/CT in the evaluation of various cancer types, especially in gastric cancer (GC).By comprehensively reviewing and analysing the differences between 68 Ga-FAPI and 18 F-FDG in GC, some evidence is provided to foster the broader clinical application of FAPI PET imaging.Methods: In this review, studies published up to July 3, 2023, that employed radionuclide labelled FAPI as a diagnostic radiotracer for PET in GC were analysed.These studies were sourced from both the PubMed and Web of Science databases.Our statistical analysis involved a bivariate meta-analysis of the diagnostic data and a meta-analysis of the quantitative metrics.These were performed using R language.Results: The meta-analysis included 14 studies, with 527 patients, of which 358 were diagnosed with GC.Overall, 68 Ga-FAPI showed higher pooled sensitivity (0.84 [95% CI 0.67-0.94]vs. 0.46 [95% CI 0.32-0.60]),specificity (0.91 [95% CI 0.76-0.98]vs. 0.88 [95% CI 0.74-0.96])and area under the curve (AUC) (0.92 [95% CI 0.77-0.98]vs. 0.52 [95% CI 0.38-0.86])than 18 F-FDG.The evidence showed superior pooled sensitivities of 68 Ga-FAPI PET over 18 F-FDG for primary tumours, local recurrence, lymph node metastases, distant metastases, and peritoneal metastases.Furthermore, 68 Ga-FAPI PET provided higher maximum standardized uptake value (SUVmax) and tumour-to-background ratios (TBR).For bone metastases, while 68 Ga-FAPI PET demonstrated slightly lower patient-based pooled sensitivity (0.93 vs. 1.00), it significantly outperformed 18 F-FDG in the lesion-based analysis (0.95 vs. 0.65).However, SUVmax (mean difference ) and TBR .80]) of bone metastases showed no significant difference between 68 Ga-FAPI PET/CT and 18 F-FDG PET/CT.Conclusion: Compared with 18 F-FDG, 68 Ga-FAPI PET imaging showed improved diagnostic accuracy in the evaluation of GC.It can be effectively applied to the early diagnosis, initial staging, and detection of recurrence/metastases of GC. 68 Ga-FAPI may have the potential of replacing 18 F-FDG in GC in future applications.
Tuning ultrasmall theranostic nanoparticles for MRI contrast and radiation dose amplification
Authors: Needa Brown, Paul Rocchi, Léna Carmès, Romy Guthier, Meghna Iyer, Léa Seban, Toby Morris, Stephanie Bennett, Michael Lavelle, Johany Penailillo, Ruben Carrasco, Chris Williams, Elizabeth Huynh, Zhaohui Han, Evangelia Kaza, Tristan Doussineau, Sneh M. Toprani, Xingping Qin, Zachary D. Nagel, Kristopher A. Sarosiek, Agnès Hagège, Sandrine Dufort, Guillaume Bort, François Lux, Olivier Tillement, Ross Berbeco
Journal: Theranostics (2023)

Background:The introduction of magnetic resonance (MR)-guided radiation treatment planning has opened a new space for theranostic nanoparticles to reduce acute toxicity while improving local control.In this work, second-generation AGuIX ® nanoparticles (AGuIX-Bi) are synthesized and validated.AGuIX-Bi are shown to maintain MR positive contrast while further amplifying the radiation dose by the replacement of some Gd 3+ cations with higher Z Bi 3+ .These next-generation nanoparticles are based on the AGuIX ® platform, which is currently being evaluated in multiple Phase II clinical trials in combination with radiotherapy.Methods: In this clinically scalable methodology, AGuIX ® is used as an initial chelation platform to exchange Gd 3+ for Bi 3+ .AGuIX-Bi nanoparticles are synthesized with three ratios of Gd/Bi, each maintaining MR contrast while further amplifying radiation dose relative to Bi 3+ .Safety, efficacy, and theranostic potential of the nanoparticles were evaluated in vitro and in vivo in a human non-small cell lung cancer model. Results:We demonstrated that increasing Bi 3+ in the nanoparticles is associated with more DNA damage and improves in vivo efficacy with a statistically significant delay in tumor growth and 33% complete regression for the largest Bi/Gd ratio tested.The addition of Bi 3+ by our synthetic method leads to nanoparticles that present slightly altered pharmacokinetics and lengthening of the period of high tumor accumulation with no observed evidence of toxicity.Conclusions: We confirmed the safety and enhanced efficacy of AGuIX-Bi with radiation therapy at the selected ratio of 30Gd/70Bi.These results provide crucial evidence towards patient translation.
Targeting materials and strategies for RNA delivery
Authors: Lixin Lin, Kexin Su, Qiang Cheng, Shuai Liu
Journal: Theranostics (2023)

RNA-based therapeutics have shown great promise in various medical applications, including cancers, infectious diseases, and metabolic diseases.The recent success of mRNA vaccines for combating the COVID-19 pandemic has highlighted the medical value of RNA drugs.However, one of the major challenges in realizing the full potential of RNA drugs is to deliver RNA into specific organs and tissues in a targeted manner, which is crucial for achieving therapeutic efficacy, reducing side effects, and enhancing overall treatment efficacy.Numerous attempts have been made to pursue targeting, nonetheless, the lack of clear guideline and commonality elucidation has hindered the clinical translation of RNA drugs.In this review, we outline the mechanisms of action for targeted RNA delivery systems and summarize four key factors that influence the targeting delivery of RNA drugs.These factors include the category of vector materials, chemical structures of vectors, administration routes, and physicochemical properties of RNA vectors, and they all notably contribute to specific organ/tissue tropism.Furthermore, we provide an overview of the main RNA-based drugs that are currently in clinical trials, highlighting their design strategies and tissue tropism applications.This review will aid to understand the principles and mechanisms of targeted delivery systems, accelerating the development of future RNA drugs for different diseases.
Histone deacetylase-mediated tumor microenvironment characteristics and synergistic immunotherapy in gastric cancer
Authors: Yilin Lin, Xiangxiang Jing, Zhihua Chen, Xiaoxian Pan, Duo Xu, Xiang Yu, Fengyun Zhong, Long Zhao, Changjiang Yang, Bo Wang, Shan Wang, Yingjiang Ye, Zhanlong Shen
Journal: Theranostics (2023)

Background: Studies have shown that the expression of histone deacetylases (HDACs) is significantly related to the tumor microenvironment (TME) in gastric cancer. However, the expression of a single molecule or several molecules does not accurately reflect the TME characteristics or guide immunotherapy in gastric cancer. Methods: We constructed an HDAC score (HDS) based on the expression level of HDACs. The single-cell transcriptome was used to analyze the underlying factors contributing to differences in immune infiltration between patients with a high and low HDS. In vitro and in vivo experiments validated the strategy of transforming cold tumors into hot tumors to guide immunotherapy. Results: According to the expression characteristics of HDACs, we constructed an HDS model to characterize the TME. We found that patients with a high HDS had stronger immunogenicity and could benefit more from immunotherapy than those with a low score. The AUC value of the HDS combined with the combined positive score (CPS)for predicting the efficacy of immunotherapy was as high as 0.96. By single-cell and paired bulk transcriptome sequencing analysis, we found that the infiltration levels of CD4+ T cells, CD8+ T cells and NK cells were significantly decreased in the low HDS group, which may be induced by MYH11+ fibroblasts, CD234+ endothelial cells and CCL17+ pDCs via the MIF signaling pathway. Inhibition of the MIF signaling pathway was confirmed to potentially enhance immune infiltration. In addition, our analysis revealed that GPX4 inhibitors might be effective for patients with a low HDS. GPX4 knockout significantly inhibited PD-L1 expression and promoted the infiltration and activation of CD8+ T cells. Conclusion: We constructed an HDS model based on the HDAC expression characteristics of gastric cancer. This model was used to evaluate TME characteristics and predict immunotherapy efficacy. Inhibition of the MIF signaling pathway in the TME and GPX4 expression in tumor cells may be an important strategy for cold tumor synergistic immunotherapy for gastric cancer.
Functional mass spectrometry imaging maps phospholipase-A2 enzyme activity during osteoarthritis progression
Authors: Xiwei Fan, Reuben S. E. Young, Antonia Rujia Sun, Brett R. Hamilton, Udhaya Nedunchezhiyan, Ross Crawford, Stephen J. Blanksby, Indira Prasadam
Journal: Theranostics (2023)

Background: Enzymes are central components of many physiological processes, and changes in enzyme activity are linked to numerous disease states, including osteoarthritis (OA). Assessing changes in enzyme function can be challenging because of difficulties in separating affected tissue areas that result in the homogenisation of healthy and diseased cells. Direct correlation between spatially-resolved enzyme distribution(s) and diseased cells/tissues can thus lead to advances in our understanding of OA pathophysiology. Herein, we present a method that uses mass spectrometry imaging (MSI) to visualise the distribution of lipase enzymes and their downstream lipid products in fresh bone and cartilage tissue sections. Immunohistostaining of adjacent tissue sections was then used to identify OA cells/tissues, which were then statistically correlated with molecular-level images. Methods: MSI was used to image lipase enzymes, their substrates, and their metabolic products to validate enzymatic activity and correlate to OA regions determined by immunohistochemistry (IHC). Based on the modified Mankin score, six non-OA and OA patient-matched osteochondral samples were analysed by matrix-assisted laser desorption/ionisation mass spectrometry imaging (MALDI-MSI). Due to the involvement of phospholipase A2 (PLA2) in inflammatory pathways, explant tissues were treated with IL-1β to mimic inflammation observed in OA. Bovine explant tissues were then subject to MSI methods to observe the spatial distribution of PLA2. Results: Compared with non-OA samples, OA samples showed an elevated level of multiple arachidonic acid (AA)-containing phospholipids (P < 0.001), in which the elevation in the surface and deep layer cartilage of OA tissues is correlated to elevated PLA2 activity (P < 0.001). Bovine explant tissues treated with IL-1β to mimic OA pathophysiology validated these results and displayed elevated PLA2 levels in OA mimic samples relative to the controls (P < 0.001). It was established that the PLA2G2A isoform specifically was responsible for PLA2 enzyme activity changes in OA tissues (P < 0.001). Conclusion: Our results present a reliable method for imaging enzyme dynamics in OA cartilage, which sets up the foundation for future spatial enzyme dynamics in the OA field. We demonstrated that OA patients exhibit increased expression of PLA2G2A at the superficial and deep cartilage zone that degrades cartilage differently at the spatial level. A tissue-specific PLA2G2A precision inhibition may be the potential target for OA.
Novel pH-activatable NIR fluorogenic spray mediated near-instant and precise tumor margins identification in human cancer tissues for surgical resection
Authors: Zhongyuan Xu, Jianqiang Qian, Hongmei Wu, Chi Meng, Qian Ding, Weizhi Tao, Chang-Chun Ling, Jun Chen, Peng Li, Yumin Yang, Yong Ling
Journal: Theranostics (2023)

Rationale: Challenges such as developing a universal tumor-specific probe for tumor margin identification in diverse tumors with an easy-operative and fast-imaging pattern still exist. Hence, in the present study, a rapidly "off-on" near-infrared (NIR) fluorescent probe NBD with pH-activatable fluorescence and a large Stokes shift was constructed for spray mediated near-instant and precise clinical tumor margins identification. Methods: NBD was designed and synthesized by introducing both diphenyl amino group and benzo[e]indolium to β-carboline at C-6 and C-3 positions respectively. The optical properties of NBD was characterized by absorption spectra, fluorescence spectra. Subsequently, we investigated its pH-dependent mechanism by 1H NMR and density functional theory (DFT) calculation. NBD was further under deeper investigation into its imaging performance in nude mice models (subcutaneous, orthotopic, metastatic tumor), and clinical tissues from patients with three clinically representative tumors (liver cancer, colon cancer, and lung cancer). Results: It was found that NBD had NIR fluorescence (742 nm), a large Stokes shift (160 nm), and two-photon absorbance (1040 nm). Fluorescence quantum yield (ФF) increased by 5.5-fold when pH decreased from 7.4 to 4.0, to show pH-dependent property. Furthermore, NBD could not only selectively light up all four cancer cell lines, but also delineate xenograft tumor and orthotopic microtumor to guide surgical tumor resection, and track metastatic tissues. Particularly, after simple topical spray (three minutes later), NBD could rapidly and precisely distinguish the boundary ranges of three kinds of clinical cancer specimens including liver, colon, and lung cancers, with high tumor-to-normal tissue signal ratios (6.48~9.80). Conclusions: Therefore, the proposed fluorescent probe NBD may serve as a versatile NIR fluorogenic spray for the near-instant visualization of tumor margins and assisting surgeons in surgerical resection of clinical cancers.